Use of CXCR2 Antagonists For The Prevention and/or Treatment of Chemotherapy Induced Peripheral Neuropathy (CIPN)

Abstract

The invention relates to the use of a CXCR2 antagonist for the prevention and/or treatment of chemotherapy induced peripheral neuropathy (CIPN).

1 - 25 . (canceled) 
     
     
         26 . A method for prevention and/or treatment of CIPN in a human in need thereof comprising administering a CXCR2 antagonist. 
     
     
         27 . The method according to  claim 26 , wherein the method is for prevention of CIPN. 
     
     
         28 . The method according to  claim 26 , wherein the CIPN is caused by a platinum-containing chemotherapeutic agent 
     
     
         29 . The method according to  claim 26 , wherein the CIPN is caused by oxaliplatin. 
     
     
         30 . The method according to  claim 26 , wherein the CXCR2 antagonist has a pIC50 value against the CXCR2 receptor of greater than or equal to 7.0 as measured in a CXCR2 receptor binding assay. 
     
     
         31 . The method according to  claim 26 , wherein the CXCR2 antagonist has a pIC50 value against the CXCR2 receptor of greater than or equal to 7.0 as measured in assay a). 
     
     
         32 . The method according to  claim 26 , wherein the CXCR2 antagonist has a pA2 value against the CXCR2 receptor of greater than or equal to 8.0 as measured in assay b). 
     
     
         33 . The method according to  claim 26 , wherein the CXCR2 antagonist has a pIC50 value against the CXCR2 receptor of greater than or equal to 8.0 as measured in assays c). 
     
     
         34 . The method according to  claim 26 , wherein the CXCR2 antagonist has a pIC50 value against the CXCR2 receptor of greater than or equal to 5.0 as measured in assay d) 
     
     
         35 . The method according to  claim 26 , wherein the CXCR2 antagonist has a selectivity for CXCR2 over CXCR1 of greater than or equal to 29 fold. 
     
     
         36 . The method according to  claim 26 , wherein the CXCR2 antagonist has solubility of 10 μg/ml. 
     
     
         37 . The method according to  claim 26 , wherein the CXCR2 antagonist has a membrane permeability of Log D 7.4  of −2 to +4. 
     
     
         38 . The method according to  claim 26 , wherein the CXCR2 antagonist is selected from the group consisting of:
 1-(4-chloro-2-hydroxy-3-(piperazin-1-ylsulfonyl)phenyl)-3-(2-chloro-3-fluorophenyl)urea of Formula (A)   
       
         
           
           
               
               
           
         
         1-(4-chloro-2-hydroxy-3-(piperidin-3-ylsulfonyl)phenyl)-3-(3-fluoro-2-methylphenyl)urea of Formula (B) 
       
       
         
           
           
               
               
           
         
         1-(4-chloro-2-hydroxy-3-(((R)-3-methyltetrahydrofuran-3-yl)sulfonyl)phenyl)-3-((R)-2-methylcyclopent-2-en-1-yl)urea of Formula (C) 
       
       
         
           
           
               
               
           
         
         1-(4-chloro-3-((1,4-dimethylpiperidin-4-yl)sulfonyl)-2-hydroxyphenyl)-3-(2-chloro-3-fluorophenyl)urea of Formula (D) 
       
       
         
           
           
               
               
           
         
         (R)-1-(4-chloro-2-hydroxy-3-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)phenyl)-3-(2-chlorocyclopent-2-en-1-yl)urea of Formula (E) 
       
       
         
           
           
               
               
           
         
         (R)-1-(3-(tert-butylsulfonyl)-4-cyano-2-hydroxyphenyl)-3-(2-methylcyclopent-2-en-1-yl)urea of Formula (F) 
       
       
         
           
           
               
               
           
         
         1-(4-chloro-2-hydroxy-3-((trans-3-(pyrrolidin-1-yl)cyclobutyl)sulfonyl)phenyl)-3-((R)-2-methylcyclopent-2-en-1-yl)urea of Formula (G) 
       
       
         
           
           
               
               
           
         
         1-(4-chloro-3-((trans-3-(dimethylammo)cyclobutyl)sulfonyl)-2-hydroxyphenyl)-3-((R)-2-methylcyclopent-2-en-1-yl)urea of Formula (H) 
       
       
         
           
           
               
               
           
         
         (R)-1-(4-chloro-3-((1,1-difluoroethyl)sulfonyl)-2-hydroxyphenyl)-3-(2-methylcyclopent-2-en-1-yl)urea of Formula (I) 
       
       
         
           
           
               
               
           
         
         1-(4-chloro-2-hydroxy-3-(((S)-3-methyltetrahydrofuran-3-yl)sulfonyl)phenyl)-3-((R)-2-methylcyclopent-2-en-1-yl)urea of Formula (J) 
       
       
         
           
           
               
               
           
         
         1-(4-chloro-2-hydroxy-3-(((S)-3-methyltetrahydrofuran-3-yl)sulfonyl)phenyl)-3-((R)-2-chlorocyclopent-2-en-1-yl)urea of Formula (K) 
       
       
         
           
           
               
               
           
         
       
       and
 1-(4-chloro-2-hydroxy-3-(((R)-3-methyltetrahydrofuran-3-yl)sulfonyl)phenyl)-3-((R)-2-chlorocyclopent-2-en-1-yl)urea of Formula (L) 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The method according to  claim 26 , wherein the CXCR2 antagonist is 1-(4-chloro-2-hydroxy-3-(piperazin-1-ylsulfonyl)phenyl)-3-(2-chloro-3-fluorophenyl)urea of Formula (A) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         40 . The method according to  claim 26 , wherein the CXCR2 antagonist is 1-(4-chloro-2-hydroxy-3-(piperidin-3-ylsulfonyl)phenyl)-3-(3-fluoro-2-methylphenyl)urea of Formula (B) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         41 . The method according to  claim 26 , wherein the CXCR2 antagonist is 1-(4-chloro-2-hydroxy-3-(((S)-3-methyltetrahydrofuran-3-yl)sulfonyl)phenyl)-3-((R)-2-methylcyclopent-2-en-1-yl)urea of Formula (J) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         42 . A combination comprising a) a CXCR2 antagonist and b) one or more primary chemotherapeutic agent of platinum compounds. 
     
     
         43 . The combination according to  claim 42 , wherein the chemotherapeutic agent is selected from the group consisting of oxaliplatin, taxanes, vinca alkaloids, thalidomide and bortezomib. 
     
     
         44 . The combination according to  claim 42 , wherein the primary chemotherapeutic agent is oxaliplatin. 
     
     
         45 . The combination according to  claim 42 , wherein the CXCR2 antagonist is administered before or at the same time as the one or more primary chemotherapeutic agent.